What every physician needs to know:

Millions of people travel to high altitude every year for recreation, exploration, and work. Ascent to high altitude is associated with physiological changes that may manifest as altitude-related illness. Altitude-related illnesses range from acute mountain sickness, which is common and usually mild, to life-threatening high-altitude pulmonary edema and high-altitude cerebral edema.

Although altitude-related illness has been documented at altitudes as low as 2000 meters, most cases occur at altitudes of greater than 2500 meters. The incidence increases with increasing altitude.

This discussion focuses on the diagnosis, classification, prevention, and treatment of altitude-related illnesses. The most effective means of addressing this group of disorders is through proper education, prevention, and prophylaxis. An important principle to keep in mind when considering management of the most severe of these disorders is that, the safest and surest treatment is descent to lower altitude.

Classification:

The triad of disorders typically associated with ascent to altitude consists of:

Acute Mountain Sickness (AMS)

High-Altitude Pulmonary Edema (HAPE)

High-Altitude Cerebral Edema (HACE)

Travel to high altitude is also associated with an increased incidence of thromboembolic events, including stroke and transient ischemic attack (TIA), as well as exacerbations of pre-existing respiratory and cardiovascular disorders.

Are you sure your patient has high-altitude illness? What should you expect to find?

The Lake Louise Consensus Group guidelines provide a unified set of diagnostic criteria for acute mountain sickness (AMS). AMS is diagnosed by the presence of headache in an un-acclimatized person recently arrived at an altitude of over 2500 meters when the headache occurs in conjunction with one or more of the following symptoms:

gastrointestinal symptoms (nausea, vomiting, anorexia)

insomnia

dizziness

fatigue or lassitude

High-altitude pulmonary edema (HAPE) typically presents with a dry cough, dyspnea on exertion, and a decrease in exercise tolerance beginning two to five days after arrival at altitude. Left untreated, HAPE can progress and lead to resting shortness of breath, orthopnea, and the development of cough with pink, frothy sputum. The patient may be cyanotic, tachycardic, and tachypneic; crackles may be heard over the mid lung fields.

High-altitude cerebral edema (HACE) is an encephalopathy that is often associated with AMS or HAPE. Patients may exhibit ataxia and a depressed level of consciousness, which may progress to stupor or coma. Clinical findings include vomiting and exam findings of retinal hemorrhages and papilledema. Seizures and cranial nerve palsies resulting from increased intracranial pressure are rare.

Although several different scoring protocols may be employed for assessing AMS, the Lake Louise Guidelines are simple, widely used, and effective for assessing acute altitude illness at varying levels of altitude (PUBMED:9856545).

The Lake Louise Score is useful for grading AMS and for longitudinally following the course of illness at a given altitude.

The symptom score ranges from 0-15; 0-5 is considered mild AMS, while a score of 6 or higher is considered moderate or severe AMS. Clinical findings, including changes in mental status and ataxia, are also relevant and may provide supplemental information.

Symptoms:

Headache:

0 = none

1 = mild

2 = moderate

3 = severe/incapacitating

Gastrointestinal:

0 = good appetite

1 = poor appetite or nausea

2 = moderate nausea or vomiting

3 = severe nausea or vomiting

Fatigue and/or weakness:

0 = none

1 = mild

2 = moderate

3 = severe

Dizziness or light headedness:

0 = none

1 = mild

2 = moderate

3 = severe

Difficulty sleeping:

0 = slept as well as usual

1 = did not sleep as well as usual

2 = woke many times; poor night's sleep

3 = unable to sleep

Clinical Findings:

Change in mental status:

0 = no change

1 = lethargy/lassitude

2 = disorientation/confusion

3 = stupor/semiconsciousness

4 = coma

Ataxia (heel-to-toe walking):

0 = none

1 = use of balancing maneuvers

2 = steps off the line

3 = falls down

4 = unable to stand

Beware: Other diseases can mimic altitude-related illness:

Since many of the findings of altitude-related illnesses are non-specific, the differential diagnosis may be extensive. The diagnosis of altitude-related illness should be questioned if symptoms develop more than three days after arrival at a given altitude, if they fail to respond to descent or administration of supplemental oxygen or dexamethasone, or if they are associated with atypical findings, such as substernal chest pain or focal neurologic deficits.

AMS may be confused with dehydration, exhaustion, diabetic ketoacidosis, alcohol-associated "hangover," hypoglycemia, hyponatremia, hypothermia, or viral/bacterial illnesses. Many of the symptoms associated with these disorders are likely to occur concurrently with AMS, particularly dehydration, exhaustion, and hypothermia, further complicating definitive diagnosis.

Encephalopathy from any cause may mimic HACE. Acute psychosis, intracranial vascular malformation, intracranial mass lesions, carbon monoxide poisoning, infection of the central nervous system, migraine, seizure, stroke, and transient ischemic attacks are all potential confounding disorders and must be considered in the differential diagnosis.

How and/or why did the patient develop altitude-related illness?

The incidence and severity of altitude-related illnesses are dependent on several factors: rate of ascent, maximum altitude attained, altitude at which the subject sleeps, degree of physical exertion at altitude, and individual susceptibility.

Rate of ascent seems to be a critical component in the development of AMS. Hiking to high altitude, rather than rapid ascent by motor vehicle or plane, for example, reduces the incidence of AMS. The incidence of AMS also increases with increasing altitude. For example, in one study (PUBMED:2282425), the incidence of AMS in the Alps was 9 percent at 2,850 meters, 13 percent at 3,050 meters, and 34 percent at 3,650 meters.

HAPE typically occurs at altitudes over 3,000 meters, but it has been documented to occur at altitudes as low as 1,400 meters. The reported incidence of HAPE varies widely; considerable differences have been attributed to rate of ascent and maximum altitude achieved. Estimates range from 0.2 percent in subjects hiking to 4,550 meters (PUBMED:62991) to 15 percent in those flown rapidly to 3,500 meters (PUBMED:14301200). The majority of deaths attributable to high-altitude related illnesses are secondary to HAPE. Low atmospheric pressure results in hypoxia, which causes regional heterogeneous hypoxic pulmonary vasoconstriction and venoconstriction, subsequent increased microvascular pressure and disruption of alveolar-capillary membrane. As a result, there is accumulation of cells and fluid into the alveolar space that manifests as pulmonary edema. Although not completely delineated, there is some genetic susceptibility involved and endothelin production is greater in HAPE susceptible patients with lower nitric oxide production.

HACE is much less common than AMS, occurring with an incidence of 1-2 percent; typically it is observed only at altitudes above 4,000 meters. HAPE often, but not always, precedes the development of HACE.

Despite decades of study, the pathogenesis of altitude-related illness is incompletely understood.

Which individuals are at greatest risk for developing high-altitude illness?

The most significant risk factor for predicting development of altitude-related illness is a previous history of altitude-related illness. Individuals residing at lower altitudes before ascent, those with pre-existing cardiopulmonary disease, and the obese have slightly higher rates of developing AMS; increasing age seems to provide a small degree of protection. However, aerobic fitness at sea level does not protect against development of altitude-related illness.

Guidelines proposed by the Wilderness Medicine Society stratify AMS risk as low, moderate, or high. Patients with no prior history of altitude sickness and those who ascend to less than 2800 meters are considered low risk. Patients without a history of AMS but ascend to greater than 2800 meters are considered moderate risk. Patients with a history of AMS that ascend to less than 2800 meters are considered moderate risk, and those who ascend to greater than 2800 meters are considered high risk. Any patient with a history of HACE or HAPE is considered high risk.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Patients suffering from more severe forms of altitude-related illness, such as HAPE or HACE, are frequently in austere environments where access to diagnostic studies is limited. In these cases, a diagnosis of altitude-related illness must be made on clinical grounds and treatment initiated without the benefit of confirmatory laboratory testing or diagnostic imaging.

Currently, no widely accepted confirmatory laboratory studies exist for the diagnosis of AMS, HACE, or HAPE. Laboratory abnormalities may be secondary to accompanying dehydration and stress. Arterial blood gases, particularly in HAPE, may demonstrate marked hypoxia.

What imaging studies will be helpful in making or excluding the diagnosis of altitude-related illness?

Diagnostic imaging may be unavailable in environments in which severe forms of altitude-related illness, such as HAPE or HACE, are observed. A diagnosis must be made on clinical grounds and treatment initiated empirically. When imaging modalities are available, patchy, peripheral infiltrates representing pulmonary edema are seen on chest radiographs or CTs in the early stages of HAPE. As the disorder progresses, the edema becomes homogenous and diffuse.

In AMS, MRI studies may show a mild increase in cerebral volume, possibly reflecting minor cerebral edema. Brain MRI findings in HACE are more consistent and characterized by increased T2 signal intensity in the corpus callosum and centrum semiovale, as well as micro hemorrhages in the corpus callosum.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of altitude-related illness?

No currently available non-invasive pulmonary diagnostic studies are useful in identifying AMS, HAPE, or HACE.

What diagnostic procedures will be helpful in making or excluding the diagnosis of altitude-related illness?

Altitude-related illness is a clinical diagnosis. No diagnostic procedures are available to confirm or exclude the diagnosis of AMS, HACE, or HAPE.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of altitude-related illness?

None are helpful in the diagnosis of altitude-related illness. However pathology studies in patients who have died from HACE have shown diffuse ring hemorrhages as well as microhemorrhages in the corpus callosum.

If you decide the patient has disease acute mountain sickness, how should the patient be managed?

The best management of high altitude-related illness is prevention. Slow ascent profiles may help minimize the risk of developing AMS. At above 3000 meters, sleeping elevation should not be increased by more than 500 meters per day; a rest day with no elevation gain should be planned every 3-4 days.

Prevention of Altitude-Related Illness

For those at moderate or high risk of developing AMS, according to the Wilderness Mountain Society criteria, pharmacological prophylaxis may be considered:

Acetazolamide is effective with a low risk of side effects. Prophylactic doses of acetazolamide are 125mg twice daily for adults and 2.5mg/kg twice daily in the pediatric population.

Although acetazolamide is the preferred agent, dexamethasone is effective in preventing AMS at a dose of 2mg every six hours or 4mg every twelve hours.

In rare circumstances that dictate the need for rapid ascent to very high altitude (over 3,500 meters) with exertion, consideration may be given to concomitant use of both acetazolamide and dexamethasone.

Prophylaxis should be started one day prior to ascent and may be stopped after 2-3 days at maximum elevation or upon initiation of descent.

Although several small studies have found a beneficial effect of the herbal supplement gingko biloba, two randomized controlled trials found no benefit over placebo.

There has been recent data that suggests ibuprofen at a dose of 1800mg a day may be effective in preventing AMS. Other recent studies have found a positive role for inhaled steroids such as budesonide for the prevention of AMS.

For patients with a history of HAPE, consideration should be given to HAPE-specific prophylaxis:

Close adherence to the ascent profile guidelines recommended for prevention of AMS are particularly important in this population.

Both acetazolamide and dexamethasone may help reduce the risk of developing HAPE, but good evidence supporting their use is lacking.

In a randomized controlled trial, the calcium channel blocker nifedipine was shown to reduce the incidence of HAPE in susceptible individuals by causing pulmonary vasodilation. The recommended dose is 60mg of the extended release formulation daily in divided doses. The drug should be started one day prior to ascent and continued until descent or following five days at altitude.

The phosphodiesterase inhibitor tadalafil appears similarly effective in a small clinical trial though the drug carries less anecdotal support than does nifedipine in preventing HAPE. The recommended dose is 10mg twice daily.

The long acting beta-2 agonist salmeterol has also been shown to be effective in the prevention of HAPE, but it is to be used as an adjunct to other treatments.

Treatment of Altitude-Related Illness

The best and most effective treatment for HACE, HAPE, or severe AMS is descent.

Since exertion may exacerbate altitude-related illness, individuals should minimize exertion during descent. The descent should be at least 1000 meters or should be continued until symptoms improve. If available, supplemental oxygen may be titrated to achieve an oxygen saturation of >90 percent.

Portable hyperbaric chambers, such as the Gamow bag, may be used for treatment of HACE or HAPE. Although effective, these devices require knowledgeable personnel for operation, and caution must be used with patients who are claustrophobic or vomiting.

While use of acetazolamide at higher doses than those used for prophylaxis has been employed in treatment of severe AMS, the agent is used primarily in mild or moderate AMS. In adults, the treatment dose for acetazolamide is 250mg twice daily.

Dexamethasone is used for moderate or severe AMS or HACE and may be administered orally, intramuscularly, or intravenously. The initial dose is 8mg, followed by 4mg every six hours until symptoms abate.

While the literature is replete with reports of other pharmacological adjuncts in the treatment of HAPE, descent and supplemental oxygen remain the mainstays of management. Nifedipine has demonstrated some efficacy in the treatment of acute HAPE with a recommended dose of 60mg of the sustained release preparation daily. Reports exist for both the use of phosphodiesterase-5-inhibitors for the treatment of HAPE as well as combination therapy with pulmonary vasodilators, acetazolamide and inhaled beta-2 agonists. Utilization of positive pressure ventilation and oxygen supplementation has also been described with beneficial effects.

What is the prognosis for patients managed in the recommended ways?

With adequate rest and adherence to treatment guidelines, individuals with mild or moderate AMS generally recover within a few days.

HACE and HAPE are often fatal if left untreated.

Clinical features of HAPE often improve after several days at a lower altitude. Neurological symptoms from HACE may take weeks or longer to resolve. Evidence is accumulating for longstanding radiographic changes on brain MRI following ascent to very high altitude. The significance of this finding requires further investigation, as no high-quality studies have addressed the long-term cognitive sequelae of ascent to very high altitudes.

After an episode of AMS, ascent can be re-attempted once symptoms have completely resolved. Non-pharmacological prophylactic measures such as slow rate of ascent and pharmacological prophylaxis should be undertaken. In the case of HAPE and HACE, it is more controversial but there are no guidelines contraindicating re-ascent. Once again, prophylactic measures must be strongly considered.

What other considerations exist for patients travelling to high altitudes?

Retinal hemorrhages are relatively common at altitude, with reported incidences up to 56% percent. Most hemorrhages are asymptomatic and transient. Their development does not mandate descent unless the macula is involved and visual acuity is compromised.

Acute exposure to the hypobaric hypoxia of altitude may exacerbate underlying chronic illness. Travel to high altitude is contraindicated in patients with pulmonary hypertension and uncompensated congestive heart failure, as the hypoxic environment increases mean pulmonary artery pressure. Patients with sickle-cell disease are prone to development of splenic infarcts and sickle-cell crises at high altitude and should avoid such environments.

Patients with severe COPD should not travel to altitude. Those with milder COPD may travel, but they should have access to pulse oximetry and supplemental oxygen.

Cardiac arrhythmias are more common at high altitude than at lower altitudes. Patients with a history of arrhythmias should have ready access to supplemental oxygen and should limit physical exertion at altitude. Patients with a history of coronary artery disease should be evaluated by a cardiologist prior to ascent to altitude; a cardiac stress test may be warranted.

Asthma is not exacerbated by ascent to high altitude; usual asthma management should be continued.

Although mild increases in blood pressure accompany ascent to altitude, the patient's sea-level antihypertensive regimen does not usually require modification.